Skeletal muscle atrophy is a frequent co-morbidity of diabetes mellitus (DM) and other chronic diseases that causes fatigue and weakness. Loss of muscle mass also is a risk factor for mortality in these conditions. Despite significant advances in understanding the mechanisms causing muscle loss,attempts to develop pharmaceutical interventions to attenuate atrophy have been unsuccessful. In contrast, exercise can have beneficial effects on muscle in chronic conditions although how its effects are achieved remains unclear. We and others have reported that the level of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha, a transcriptional coactivator protein, is decreased in skeletal muscle during DM and in cultured myotubes treated with glucocorticoids to induced insulin resistance and atrophy. This is notable because PGC-alpha expression in normal skeletal muscle is increased by exercise and transgenic overexpression of PGC-1alpha protects against muscle loss. PGC-1alpha is a critical master regulator that integrates energy and protein metabolism. It functions by inhibiting the activity of the F Box O (FOXO) transcription factors which mediate the atrophy program. Understanding how exercise maintains muscle function in DM will improve our ability to treat fatigue and weakness. To accomplish this goal, we must first understand the biochemical basis for dysregulation of PGC1alpha expression during atrophy. This project will test the hypothesis that the reduction in PGC-1alpha expression during DM-related atrophy results from abnormal signaling through one or more pathways that are regulated by calcineurin (Cn), a calcium-activated serine/threonine phosphatase. We will examine the myocyte enhancer factor 2 (MEF2) and cytoplasmic nuclear factor of activated T cells (NFATc) pathways because both transcription factors are Cn substrates that have been reported to regulate PGC-1alpha transcription in normal skeletal muscle. The third pathway to be studied is the Transducer of Regulated CREB 1 (TORC1)/cyclic AMP-responsive element (CRE)-binding protein (CREB) pathway. TORC1 is a transcription coactivator of CREB that is activated by Cn and required for PGC-1alpha expression. Our preliminary data suggests that TORC1 function is impaired during atrophy. Once the mechanisms of PGC-1alpha dysregulation are characterized, we will test whether exercise improves Cn signaling in DM mice, thus leading to an increase in muscle PGC-1alpha expression. When the aims of this project are complete, we will have identified the Cn-related pathways that are responsible for the reduction in PGC-1alpha expression, and thus contribute to atrophy. In addition, we will have determined which of these pathways in DM muscle respond to exercise. This information could be useful for designing innovative and protein-targeted treatments and rehabilitation therapies of Veterans with DM. Results of the proposed studies also may be relevant to Veteran transplant recipients whose immunosuppressive therapies include glucocorticoids and/or calcineurin inhibitors (i.e., cyclosporine A, FK506). Many transplant recipients have reduced lean body mass due the catabolic effects of chronic diseases while others are challenged to maintain their muscle mass due to maintenance prednisone therapy. Use of Cn inhibitors could have a negative impact on both types of patients. Lastly, our results could be broadly applicable to Veterans suffering from many types of debilitating diseases associated with atrophy.